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Non-specific Effects of Vaccines
INTRODUCTION
In addition to protecting against their target disease, vaccines can induce changes in the immune system that have broader effects. As early as in the 1800s, it was noted that smallpox vaccination was associated with protection against unrelated infections. In the 1930s, the term “non-specific effects” (NSE) was used to describe the observation that the reduction in all-cause mortality in infants vaccinated with bacille Calmette-Guérin (BCG) was greater than could be explained by protection against tuberculosis (TB) alone. , Other terms used to describe the immunomodulatory effects of vaccines over and above the influence on their target pathogen include “off-target effects,” “heterologous immunity,” and “accidental advantages.” , , , NSE are distinct from adverse, cross-protective and downstream indirect effects ( Fig. 3.1 ).
Reported clinical manifestations of NSE include reduced all-cause mortality, protection against unrelated infections, and reduced risk of allergic and autoimmune diseases. NSE of vaccines also include the prevention and treatment of malignancies: BCG for the treatment of noninvasive superficial bladder cancer is a licensed use of a NSE. In addition to these beneficial effects, some evidence suggests that in certain situations and settings, non-live vaccines might have detrimental NSE associated with increased all-cause mortality, a finding that has been controversial. ,
NSE have been described for many vaccines but have been most extensively studied for BCG, measles-containing vaccines (MCV), and diphtheria-tetanus-pertussis vaccine (DTP). Recent research has shed light on the molecular and immunological mechanisms that potentially underlie NSE, particularly for BCG vaccine. , The level of evidence for different vaccines and for different clinical manifestations varies considerably. Intriguing reports from observational studies led to further exploration of NSE of vaccines in cohorts and registries, randomized clinical trials and, more recently, human challenge models. This chapter focuses on human studies but there is also a large body of evidence from animal models. ,
Evidence from Clinical Studies
All-Cause Mortality
There is increasing evidence that live-attenuated vaccines (smallpox, BCG, MCV, oral poliovirus vaccine [OPV]) are associated with reduced all-cause mortality. There is also some evidence from observational studies that non-live vaccines might increase all-cause mortality. NSE seem to be largely determined by the most recent vaccine given. A meta-analysis published in 2016, following a WHO-instigated review, included 68 articles from 34 birth cohorts worldwide addressing the NSE of BCG, MCV and DTP ( Fig. 3.2 ). Of the RCTs included, two (on BCG) were judged to be at low risk of bias, and seven (on BCG or MCV) at moderate risk. All the observational studies were judged to be at high risk of bias; those at very high risk of bias were excluded from the analysis. The results are summarized in Fig. 3.2 .
Smallpox
NSEs of smallpox vaccination were noted soon after its implementation, as the vaccine was observed to protect against unrelated infections, and was associated with a greater decline in mortality than expected. This was sustained after the elimination of smallpox, with a reduced risk of hospitalization for infection. A degree of protection against human immunodeficiency virus (HIV)-1 infection has also been observed, perhaps from downregulation of the CCR5 receptor.
Bacille Calmette-Guérin Vaccine
Combining results from five RCTs, the meta-analysis reported a beneficial effect of infant BCG on all-cause mortality (relative risk [RR] 0.70, 95% confidence interval [CI] 0.49–1.01). For the two RCTs at low risk of bias, both in low birth weight (LBW) infants in Guinea Bissau, the RR was 0.52 (95% CI 0.33–0.82). A subsequent third RCT in LBW infants in Guinea-Bissau also found a beneficial effect of neonatal BCG-Denmark, and reported a pooled RR for the three trials with low risk of bias of 0.62 (95% CI 0.46–0.83). In contrast, two subsequent RCTs found no effect of BCG-Russia on neonatal mortality in LBW neonates in Indian Intensive Care Units. , In nine observational studies, the meta-analysis reported a pooled RR of 0.47 (CI 95% 0.32–0.69).
Measles-Containing Vaccines
In the meta-analysis, the pooled RR from four RCTs (three in Guinea-Bissau, one in Nigeria) for all-cause mortality in MCV-vaccinated infants was 0.74 (95% CI 0.51–1.07). Previous meta-analyses also found a non-specific beneficial effect of early MCV vaccination. , In a subsequent RCT in Burkina Faso and Guinea Bissau there was no effect of early MCV on all-cause mortality, perhaps, the authors suggested, because many participants received OPV. , In 18 observational studies, the pooled RR was 0.51 (CI 95% 0.42–0.63).
High-Titre Measles Vaccine
An early dose of high-titre measles vaccines was recommended by WHO in the early 1980s as a strategy to protect against measles in the presence of maternal measles antibodies, to minimize the period of susceptibility between loss of maternal antibody and infant vaccination. As a result of RCTs from West Africa and Haiti showing a nearly two-fold higher mortality rate in girls who had received an early dose of high-titre measles vaccine, a WHO consultation in 1992 led the Expanded Program on Immunization (EPI) to withdraw its recommendation. One hypothesis to explain the increased mortality was that it was due to the receipt of DTP shortly after the early high-titre measles vaccine: increased mortality was observed only in girls who received DTP after the early high-titre measles vaccine and not in those who received DTP before the early high-titre measles vaccine. ,
Oral Polio Vaccine
Observational studies suggest reduced all-cause mortality following OPV. One RCT compared BCG plus OPV at birth with BCG alone. A significant reduction in all-cause mortality was observed only in subgroup analysis: when OPV was given in the first 2 days of life (HR 0.58, 95% CI 0.38–0.90), particularly in boys. Another RCT comparing OPV with vitamin A at birth was stopped prematurely when mortality was found to be higher in the vitamin A group. On the basis of these studies, it has been suggested that replacing OPV with IPV might increase all-cause mortality in high-mortality settings.
Diphtheria, Tetanus, and Pertussis Vaccine
The 2016 meta-analysis reported a possible increase in all-cause mortality following (non-live) DTP vaccination of infants when combining results from 10 observational studies (RR 1.38, CI 95% 0.92–2.08). This effect was higher when a study with a high risk of bias was excluded (RR 1.53, 95% CI 1.02–2.30). This analysis has been subject to considerable debate. Some have argued that the excess mortality following DTP is even higher than suggested in the meta-analysis, as a result of the inclusion of studies at high risk of bias. The disproportionate increase in mortality following DTP in girls compared to boys has also been highlighted. , Following a SAGE review, the WHO concluded there was insufficient evidence to justify a change in vaccination schedules but indicated the need for further trials of the effect of DTP on all-cause mortality.
Other Non-live Vaccines
Observational studies have suggested an association between other non-live vaccines and increased mortality, particularly in girls. These include hepatitis B vaccine (HBV), the pentavalent vaccine (DTP- H. influenza type b-HBV), the inactivated poliovirus vaccine, and the H1N1 vaccine. An RCT evaluating the efficacy of the malaria vaccine RTS,S incidentally found a higher mortality rate in girls in the intervention group, , raising ethical concerns about ongoing RTS,S trials. , The lower than expected rate of meningitis and cerebral malaria in the control group led to the suggestion that the rabies vaccine (given to the control group) had a non-specific protective effect on all-cause mortality based on a cohort study in dogs, but a subsequent RCT of rabies vaccine reported increased all-cause mortality in female dogs.
Infections
Prevention of Infections
The reduction in neonatal and infant all-cause mortality following live vaccines (smallpox, BCG, MCV and OPV) is proposed to result from a reduction in infections other than their target pathogen, particularly respiratory tract infections, sepsis, and malaria. , , RCTs and observational trials with infection as an outcome support this hypothesis but have shown inconsistent results and there has been no systematic review.
BCG
In one RCT in Ugandan infants and two large observational studies, , BCG was associated with a lower risk of respiratory infections. In two RCTs in adults living in both high- and low-mortality settings, BCG vaccination reduced the incidence of respiratory tract infections by 70–80% compared with no BCG vaccination. , In another RCT, upper respiratory tract infections were incidentally found to be >70% lower in BCG-revaccinated adolescents compared to those receiving a placebo. However, two RCTs in low-mortality settings did not find an effect of neonatal BCG-Denmark vaccination on infant infectious diseases, although, in one trial, it did have an effect in infants whose mothers had received BCG. ,
There is also limited evidence to suggest that BCG vaccination has beneficial NSEs against leishmaniasis and malaria. One RCT and one observational study reported that BCG vaccination reduces the burden of malaria in African children. In contrast, another RCT found that BCG-Denmark revaccination of children did not reduce malaria morbidity. A human challenge study in adults reported that BCG-Bulgaria altered the clinical and immunological responses to malaria. In another human challenge model, prior vaccination with BCG-Denmark reduced yellow fever vaccine viraemia by 71% (95% CI, 6%–91%) and improved antiviral immune responses.
Observational studies suggest that multiple doses of BCG vaccine reduce recurrences of herpes labialis or herpes genitalis. However, one RCT reported the frequency of recurrence to be unchanged after a single BCG vaccination.
Measles-Containing Vaccines
In RCTs in Guinea-Bissau, early MCV reduced the risk of infection, and of subsequent hospitalization for respiratory infections. In contrast, early MCV had no effect on hospitalization in an RCT in Burkina Faso, perhaps, it has been suggested, because of concurrent OPV campaigns. In a cross-over placebo-controlled RCT in Finnish twin pairs, MMR reduced respiratory symptoms 9 days after vaccination. A number of registry-based observational studies in Europe and the United States have suggested an association between MCV and lower risk of hospitalization for respiratory infection in children. A self-controlled case series from the UK did not replicate this finding, but the methodology in that study has been questioned. ,
Other Vaccines
Reduced infections have been reported in observational studies and RCTs following OPV , and smallpox vaccination, , , both of which are live vaccines. In an RCT, an inactivated rabies vaccine did not provide protection against mild self-reported “common infectious diseases” in young healthy adults.
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